Our long term goal is to elucidate the cellular mechanism of tau toxicity, in the context of its biological function in the cell and the mechanism of tau transmission from cell to cell. We have previously shown that tau hyperphosphorylation at position 199, 212, 231 and 262, combined with the FTDP-17 mutation at the carboxyl terminus of the protein, R406W (termed here Pathological Human tau or PH-Tau) are critical for inducing a conformational change in the protein that makes it mimics the abnormal hyperphosphorylated tau from AD brain. We and others have shown that hyperphosphorylated tau from AD brains disrupts microtubules and behaves as a prion-like protein because it binds normal tau and self-aggregates in bundles of filaments. PH- Tau shares those toxic properties with pathological tau from AD patients. Abnormal tau in AD brains can be found in neurons, aggregated in filaments or soluble, as well as in cerebrospinal fluid (CSF) as a naked protein or in vesicles called exosomes. Tau uptake by different cells has been reported in vivo and in vitro. In our preliminary experiments, membrane zeiosis, or blebbing, can be observed in cells transfected with PH-Tau. Using co-cultures we found that PH-Tau can be secreted from cells and taken up by the neighboring cells. This phenomenon seems to be selective for different cell types. Besides tau function inside the neurons, tau has been reported to interact with and activate muscarinic receptors. The propagation of tau between neurons and the effects of this abnormal protein in the neurons is a key factor in the progression of AD and other tauopathies and a better understanding will play a large role in developing therapeutics. We hypothesize that changes in tau phosphorylation induces a concomitant alteration in tau conformation and biological properties, and that this modified protein gets secreted from neurons and transferred to neighboring neurons. Through this transfer mechanism, the abnormal tau can infect normal neurons in a prion-like fashion. The uptake of PH-Tau can disrupt the cytoskeleton, affect synaptic proteostasis and trigger the neurodegeneration process with a negative impact on cognitive functions and memory. This proposal will investigate the mechanism and the consequences of tau uptake by other neurons in tau transmission in vitro and in vivo by:) To determine whether vesicular, exosomal or secreted PH-Tau will transfer toxicity to healthy cells in culture and 2) Compare the spread of lentiviral expressed tau and PH-Tau in vivo. Experiments designed in this proposal will shed new light on the transmission of tau toxicity and new putative therapeutical targets. These experiments will also provide rich training opportunities for graduate and undergraduate underrepresented students, from the College of Staten Island primarily by providing support for doctoral and Master?s students.